Isobutyric acid (2R,3R,4R,5R)-5-(4-amino-2-oxo-2H-pyrimidin-1-yl)-4-fluoro-2-isobutyryloxymethyl-4-methyl-tetrahydro-furan-3-yl ester (compound 1) is a hepatitis C virus (HCV) polymerase inhibitor prodrug. Compound 1 can be prepared as described in WO2007/065829. Hepatitis C virus is a blood-borne infectious disease that affects the liver. The infection is often asymptomatic, but once established, chronic infection can cause inflammation of the liver (chronic hepatitis). No vaccine against hepatitis C virus is available.

Compound 1 is being evaluated in the clinic for the treatment of liver infection caused by hepatitis C virus. The estimated daily dose is 1 g-2 g requiring high drug loading in the drug product to provide the best treatment regimen for the patients. Compound 1 is a weak base with a pKa of 3.5 thus requiring the drug product to have an immediate release (IR) profile to overcome pH-dependent solubility limitations (see FIG. 1). As shown in FIG. 1, the drug solubility drops precipitously at pH>4 suggesting that the absorption of drug could become dissolution-rate limited at physiologically relevant pH. The high dose and need for an immediate release profile are further complicated by the low bulk density of the drug substance (0.04 to 0.3 g/cc). The conventional manufacturing technologies employing commonly used excipients require the use of multiple densification steps as well as high amounts of excipients such as binders. In addition to the multi-step manufacturing process, the high usage of binder has a negative impact on the dissolution of the product resulting in lower bioavailability.
The availability of commercially manufacturable drug products that provide the best mode of treatment for the patient is a critical component of the drug development process. The safety, efficacy and acceptability of drug can be significantly influenced by the selection of a dosage form that depends on the dose, physico-chemical, and biopharmaceutical properties of the therapeutically active agent. Use of the appropriate manufacturing technologies and pharmaceutically acceptable excipients can resolve many common problems with such compounds. For example, frequently used approaches to resolve the biopharmaceutical issues include technologies such as particle size reduction, lipid solution, conversion to solid dispersions, or the use of amorphous forms. Similarly there are well-established approaches to manage poor particulate properties e.g., flow and compaction properties by mixing with excipients and processing such as granulation and sizing of the particles. Manufacturing technologies such as granulation (dry/wet), fluid bed granulation, and high shear granulation are commonly used approaches to resolve manufacturing difficulties related to flow, content uniformity, and compression. Similarly there are many technologies available to solve poor biopharmaceutical properties of compounds. Although many technologies are available to resolve these issues, the combination of these challenges such as dose, solubility, and poor physico-chemical properties can present insurmountable difficulties in developing suitable products. Accordingly, novel approaches are frequently employed to formulate these products to deliver optimal results with respect to manufacturability, stability, bioavailability, and patient convenience.